Use of pramipexole as a treatment for cocaine craving

ABSTRACT

Disclosed herein are methods for reducing stimulant dependency or craving, involving administration of a therapeutically-effective amount of a dopamine agonist, such as pramipexole.

BACKGROUND OF THE INVENTION

[0001] This invention relates to methods for the treatment of cocainecraving.

[0002] Cocaine is a highly addictive pyschostimulant that causessensations of euphoria and craving, resulting in physiological as wellas psychological damage. Although cocaine use leads to a multitude ofphysiological complications, its primary target of action is the centralnervous system. Cocaine withdrawal following abstinence causes, amongother symptoms, an intense craving for the abused drug, which in turnfrequently results in the relapse into renewed drug use. Epidemiologicalstudies point to a high incidence of multiple substance abuse amongcocaine users, a finding that has significant societal and medicalrepercussions.

[0003] To date, approved pharmacotherapies for cocaine abuse anddependence have proven scarce despite the acute need for such therapies.

SUMMARY OF THE INVENTION

[0004] In general, the invention features methods for treating stimulantdependencies, such as cocaine craving, by administering atherapeutically-effective amount of a dopamine agonist, for example,pramipexole.

[0005] In one aspect, the invention provides a method of treating apatient (for example, a human) with a stimulant dependency byadministering a therapeutically-effective amount of pramipexole to thepatient. In preferred embodiments of this aspect, the stimulantdependency is a stimulant craving and the stimulant is cocaine.

[0006] In a related aspect, the invention provides a method of treatinga human diagnosed with cocaine craving by administering atherapeutically-effective amount of pramipexole to the human.

[0007] In preferred embodiments of both of the above aspects of theinvention, the method further includes administering atherapeutically-effective amount of an antidepressant or ananticonvulsant, for example, lamotrigine.

[0008] By “treating” is meant the medical management of a patient withthe intent that a cure, amelioration, or prevention of a dependency or arelapse or associated disease, pathological condition, or disorder willresult. This term includes active treatment, that is, treatment directedspecifically toward improvement of the dependency or associated cure ofa disease, pathological condition, or disorder, and also includes causaltreatment, that is, treatment directed toward removal of the cause ofthe dependency or associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe dependency, disease, pathological condition, or disorder; preventivetreatment, that is, treatment directed to prevention of the dependencyor associated disease, pathological condition, or disorder; andsupportive treatment, that is, treatment employed to supplement anotherspecific therapy directed toward the improvement of the dependency orassociated disease, pathological condition, or disorder. The term“treating” also includes symptomatic treatment, that is, treatmentdirected toward constitutional symptoms of the dependency or anassociated disease, pathological condition, or disorder.

[0009] By “stimulant” is meant any substance that temporarily increasesfunctional activity, and preferably cardiac, respiratory, cerebral,nervous, vascular, motor, or vasomotor functional activity. Preferredstimulants include, without limitation, cocaine, amphetamines,methamphetamine, and methylphenitale.

[0010] By “therapeutically-effective amount” is meant an amount of apramipexole compound sufficient to produce a healing, curative, orameliorative effect either in the treatment of a stimulant dependency orin the symptoms of a stimulant dependency, for example, cocaine craving.

[0011] By “dependency” is meant any form of behavior that indicates analtered or reduced ability to make decisions resulting, at least inpart, from the use of stimulants. Representative forms of dependencybehavior may take the form of antisocial, inappropriate, or illegalbehavior and include those behaviors directed at the desire, planning,acquiring, and use of stimulants. This term also includes the psychiccraving for a drug that may or may not be accompanied by a physiologicaldependency, as well as a state in which there is a compulsion to take adrug, either continuously or periodically, in order to experience itspsychic effects or to avoid the discomfort of its absence. Forms of“dependency” include habituation, that is, an emotional or psychologicaldependence on a compound to obtain relief from tension and emotionaldiscomfort, as well as physical or physiological dependence, that is,use of a compound to prevent withdrawal symptoms.

[0012] By “craving” is meant a behavior that reflects a consumingdesire, longing, or yearning for a stimulant. This term may refer toaspects of behaviors that are components of a dependency.

[0013] The present invention provides a number of advantages.Importantly, it provides one of the first therapeutics for the treatmentof stimulant cravings (such as cocaine craving). In addition, thepramipexole utilized herein is non-toxic, is pharmocokineticallyunderstood, and is known to be well tolerated by humans, as is evidencedby its approval for the treatment of Parkinson's Disease.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 is a schematic illustration of the molecular structure ofpramipexole, marketed as Mirapex in the United States.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The invention described herein features methods involving theadministration of pramipexole (or other dopamine-D3/D2 agonists) for thetreatment of stimulant dependency, and preferably for the treatment ofcocaine craving and its symptoms, as well as cocaine dependency andassociated self-destructive behaviors.

[0016] Described below is an example of the successful use ofpramipexole for the treatment of cocaine craving and related symptoms.This example is provided for the purpose of illustrating the inventionand should not be construed as limiting.

Treatment of Cocaine Craving Using Pramipexole

[0017] Mr. A, a 34 year-old single, successful business man, wasreferred for evaluation of possible bipolar disorder. Currentlydepressed, he had in the previous year brought financial ruin on himselfby a pattern of cocaine freebasing and sexual and other extravagancethat absorbed nearly one million dollars.

[0018] Along with current major depression, persisting cocaine cravingbut rare use, and a question of past primary or secondary (to substanceabuse) mania, he manifested an extraordinary movement disorder withconstant restlessness and thrashing of his legs, leaving the inneraspects of his knees and thighs bruised and discolored with hematomas invarious stages of evolution and resolution.

[0019] For the restless legs, he had consulted a neurologist whodiagnosed “pre-parkinsonism” presumed secondary to neurological damagefrom cocaine. The disfiguring movements limited his ability to return toand conduct business.

[0020] Previously, he had failed to respond to or tolerate most of thenew generation of antidepressants. Treatment was begun with lamotrigineup to 200 mg with modest improvement in mood. Given his severe restlesslegs syndrome and persisting depression, pramipexole was added, titeatedto 1.5 mg a day in divided doses.

[0021] In response to this treatment, his leg movements quietedsubstantially, his mood brightened, and he reported that these were thefirst days in a year that he awoke without craving cocaine, a benefitsustained for one year on this drug, combined with 75 mg of lamotrigine.During the subsequent year, Mr. A. reported one day of non-compliancewhen he was out of town without his medication. That night, for thefirst time, he dreamt about cocaine and the next day experienced arenewed craving on awakening which resolved when treatment was restored.

[0022] Although he faces an array of financial and business challenges,his mood following treatment is nearly euthymic, his leg movements atworst resemble mild restlessness, and his cocaine craving remainsabolished.

[0023] These dramatic results demonstrate that dopamine agonists, likepramipexole, represent treatments for cocaine craving, and may beparticularly useful for patients with comorbid refractory depression.

Pramipexole and Other Dopamine Agonists

[0024] The synthesis of pramipexole is described in U.S. Pat. No.4,886,812 and European Patent 186 087. Pramipexole is a non-ergotderivative which may be used at a range of between about 1.5 mg to 6.0mg per day) and is preferably administered between about 1.5 mg and 4.5mg per day. Higher dosages may be used with the concomitant risk ofpotential side effects.

[0025] Other formulations for treatment or prevention of stimulantdependency or craving, such as cocaine craving, as described herein, maytake the form of a dopamine agonist compound that may be combined with apharmaceutically-acceptable diluent, carrier, stabilizer, or excipient.Conventional pharmaceutical practice is employed to provide suitableformulations or compositions to administer such compositions topatients. Oral administration is preferred, but any other appropriateroute of administration may be employed, for example, parenteral,intravenous, subcutaneous, intramuscular, intracranial, intraorbital,ophthalmic, intraventricular, intracapsular, intraspinal,intracisternal, intraperitoneal, intranasal, or aerosol administration.Therapeutic formulations may be in the form of liquid solutions orsuspensions (as, for example, for intravenous administration); for oraladministration, formulations may be in the form of liquids, tablets orcapsules; and for intranasal formulations, in the form of powders, nasaldrops, or aerosols.

[0026] Methods well known in the art for making formulations aredescribed, for example, in “Remington: The Science and Practice ofPharmacy” (19th ed.) ed. A. R. Gennaro A. R., 1995, Mack PublishingCompany, Easton, Pa. Formulations for parenteral administration may, forexample, contain excipients, sterile water, saline, polyalkylene glycolssuch as polyethylene glycol, oils of vegetable origin, or hydrogenatednapthalenes.

[0027] If desired, slow release or extended release delivery systems maybe utilized. Biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers may be used to control the release of the compounds. Otherpotentially useful parenteral delivery systems include ethylene-vinylacetate copolymer particles, osmotic pumps, implantable infusionsystems, and liposomes. Formulations for inhalation may containexcipients, for example, lactose, or may be aqueous solutionscontaining, for example, polyoxyethylene-9-lauryl ether, glycocholateand deoxycholate, or may be oily solutions for administration in theform of nasal drops, or as a gel.

[0028] In general, a dopamine agonist for use in the methods of theinvention is administered at a dosage appropriate to the effect to beachieved and is typically administered in unit dosage form. As notedabove, the preferred route of administration for most indications isoral.

[0029] An effective quantity of a dopamine agonist-containing compoundof the invention is employed to treat the stimulant dependency orCraving, for example, cocaine craving as described herein. The exactdosage of the compound may be dependent, for example, upon the age andweight of the recipient, the route of administration, and the severityand nature of the symptoms to be treated. In general, the dosageselected should be sufficient to prevent, ameliorate, or treat thecondition, or one or more symptoms thereof, without producingsignificant toxic or undesirable side effects.

Combination with Other Therapeutics

[0030] One particular source of pramipexole is Pharmacia & Upjohn, Inc.which markets Mirapex (Pramipexole Dihydrochloride) tablets which havethe molecular structure shown in FIG. 1. Examples of other dopamineagonists include, but are not limited to, amantadine, bromocriptine,cabergoline, lisuride, pergolide, ropinirole, quinpirole, orquinelorane. Pramipexole, or any other dopamine agonist, may beadministered as a monotherapy, or in combination with other compounds,for the treatment of multiple substance abuse or other physiological orpsychological conditions.

[0031] In one particular example, the dopamine agonist (e.g.pramipexole) may be administered in combination with an antidepressant,anticonvulsant antianxiety, antimanic, antipyschotic, antiobsessional,sedative-hypnotic, or stimulant medication. Examples of thesemedications include, but are not limited to, the antianxiety medicationsalprazolam, buspirone hydrochloride. chlordiazepoxide, chlordiazepoxidehydrochloride, clorazepate dipotassium, desipramine hydrochloride,diazepam, halazepam, hydroxyzine hydrochloride, hydroxyzine pamoate,lorazepam, meprobamate, oxazepam, prazepam, prochlorperazine maleate,prochlorperazine, prochlorperazine edisylate, and trimipramine maleate;the anticonvulsants amobarbital, amobarbital sodium, carbamazepine,chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepatedipotassium, diazepam, divalproex sodium, ethosuximide, ethotoin,gabapentin, lamotrigine, magnesium sulfate, mephenyloin, mephobarbital,methsuximide, paramethadione, pentobarbital sodium, phenacemide,phenobarbital, phenobarbital sodium, phensuximide, phenyloin, phenyloinsodium, primidone, secobarbital sodium, trimethadione, valproic acid,and clonazepam; the antidepressants amitriptyline hydrochloride,amoxapine, bupropion hydrochloride, clomipramine hydrochloride,desipramine hydrochloride, doxepin hydrochloride, fluoxetine,fluvoxamine imipramine hydrochloride, imipramine pamoate, isocarboxazid,lamotrigine, maprotoline hydrochloride, nortriptyline hydrochloride,paroxetine hydrochloride, phenelzine sulfate, protriptylinehydrochloride, sertraline hydrochloride, tranylcypromine sulfate,trazodone hydrochloride, trimipramine maleate, and venlafaxinehydrochloride, the antimanic medications lithium carbonate and lithiumcitrate; the antiobsessional medications fluvoxamine, and clomipraminehydrochloride; the antipsychotic medications acetophenazine maleate,chlorpromazine hydrochloride, chlorprothixene, chlorprothixenehydrochloride, clozapine, fluphenazine decanoate, fluphenazineenathrate, fluphenazine hydrochloride, haloperidol decanoate,haloperidol, haloperidol lactate, lithium carbonate, lithium citrate,loxapine hydrochloride, loxapine succinate, mesoridazine besylate,molindone hydrochloride, perphenazine, pimozide, prochlorperazinemaleate, prochlorperazine, prochlorperazine edisylate, promazinehydrochloride, risperidone, thioridazine, thioridazine hydrochloride,thiothixene, thiothixene hydrochloride, and trifluoperzinehydrochloride; the sedative-hypnotic medications amobarbital,amobarbital sodium, amobarbital, butabarbital, chloralhydrale,chlordiazepoxide, chbordiazepoxide hydrochloride, clorazepatedipoiassium, diazepam, diphenhydramine, estazolam, ethchlorvynol,flurazepam hydrochloride, glutethimide, hydroxyzine hydrochloride,hydroxyzine pamoate, lorazepam, methotrimeprazine hydrochloride,midazolam hydrochloride, non prescription, oxazepam, pentobarbitalsodium, phenobarbital, phenobarbital sodium, quazepam, secobarbitalsodium, temazepam, triazolam, and zolpidem tartrate; and the stimulantsdextroamphetamine sulfate, methamphetamine hydrochloride,methylphenidate hydrochloride and, pemoline.

Other Embodiments

[0032] All publications and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

[0033] While the invention has been described in connection withspecific embodiments thereof, it will be understood that it is capableof further modifications and this application is intended to cover anyvariations, uses, or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent disclosure that come within know n or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe appended claims.

[0034] Other embodiments are within the claims.

What is claimed is:
 1. A method for treating a human with a stimulantdependency, said method comprising administering to said humanpramipexole in a dose ranging from 1.5 mg/day to 6.0 mg/day.
 2. Themethod of claim 1, wherein said stimulant dependency involves astimulant craving.
 3. The method of claim 1, wherein said stimulant iscocaine.
 4. The method of claim 1, wherein said pramipexole isadministered in a dose ranging from 1.5 mg/day to 4.5 mg/day.
 5. Amethod of treating a cocaine craving in a human, said method comprisingadministering to said human pramipexole in a dose ranging from 1.5mg/day to 6.0 mg/day.
 6. The method of claim 5, wherein said pramipexoleis administered in a dose ranging from 1.5 mg/day to 4.5 mg/day.
 7. Amethod for treating a human with a stimulant dependency, said methodcomprising administering to said human pramipexole, wherein saidpramipexole is administered intranasally.
 8. The method of claim 7,wherein said stimulant dependency involves a stimulant craving.
 9. Themethod of claim 8, wherein said stimulant is cocaine.
 10. The method ofclaim 7, wherein said pramipexole is administered in a dose ranging from1.5 mg/day to 6.0 mg/day.
 11. The method of claim 10, wherein saidpramipexole is administered in a dose ranging from 1.5 mg/day to 4.5mg/day.
 12. A method of treating a cocaine craving in a human, saidmethod comprising administering to said human pramipexole, wherein saidpramipexole is administered intranasally.
 13. The method of claim 12,wherein said pramipexole is administered in a dose ranging from 1.5mg/day to 6.0 mg/day.
 14. The method of claim 13, wherein saidpramipexole is administered in a dose ranging from 1.5 mg/day to 4.5mg/day.